Identifying the mechanisms of leukemia progression

项目摘要 自2002年我的实验室在所有急性巨核细胞白血病病例中发现GATA 1突变以来， 对于患有唐氏综合症的儿童，我一直站在定义特定遗传事件的最前沿， 白血病我已经广泛研究了GATA 1在正常和恶性造血中的作用，并获得了许多关于GATA 1的研究成果。 深入了解几个21号染色体基因的贡献，包括DYRK 1A，ERG和CHAF 1B， 白血病我的实验室在骨髓增生性肿瘤（MPN）领域也很有建树， 特别是巨核细胞在骨髓纤维化发病机制中的作用以及新的 治疗这种疾病。在这个R35应用程序中，我建议在未来7年内专注于我的实验室（以及 超越）对了解白血病从克隆性造血障碍进展的机制。 具体来说，我们将确定和比较儿童和成人疾病进展为急性髓系白血病的方式， 白血病我们将利用大规模CRISPR/Cas9筛选、动物模型和原始患者样本， 深入描述转化机制，重点回答三个问题：1）什么是 类似和不同的事件，促进儿童与成人血液疾病的恶性进展？（二） 肿瘤抑制基因下游通路的失调如何促进恶性肿瘤的发生？ 进展？3)哪些研究或批准的疗法可以预防进展或治疗肿瘤？的 这些问题的答案将增加我们对癌症的基本了解，揭示新的治疗靶点， 可能有助于化学预防策略。

PROJECT SUMMARY Since 2002 when my laboratory discovered GATA1 mutations in all cases acute megakaryocytic leukemia in children with Down syndrome, I have been at the forefront of defining the specific genetic events that promote leukemia. I have extensively studied the role of GATA1 in normal and malignant hematopoiesis and gained many insights into the contributions of several chromosome 21 genes, including DYRK1A, ERG and CHAF1B, in leukemia. My laboratory is also well established in the field of the myeloproliferative neoplasms (MPNs), especially in the role of megakaryocytes in the pathogenesis of myelofibrosis and the development of new therapies for this disease. In this R35 application, I propose to focus my laboratory over the next 7 years (and beyond) on understanding the mechanisms of leukemia progression from clonal hematopoietic disorders. Specifically, we will identify and compare the ways that pediatric and adult disorders progress to acute myeloid leukemia. We will leverage large scale CRISPR/Cas9 screening, animal models and primary patient samples to deeply characterize the mechanisms of transformation and focus on answering three questions: 1) What are the similar and disparate events that promote malignant progression of pediatric versus adult blood disorders? 2) How does dysregulation of pathways downstream of identified tumor suppressor genes promote malignant progression? 3) Which investigational or approved therapies can prevent progression or treat the tumors? The answers to these questions will increase our basic understanding of cancer, reveal new therapeutic targets and possibly shed light on chemoprevention strategies.